Endocrine disrupter modulation of SXR in development and lymphomagenesis

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DESCRIPTION (provided by applicant): This is an R01 application intended to test the hypothesis that loss-of-function in the steroid and xenobiotic receptor, SXR, will lead to lymphoma and leukemia in exposed individuals. Establishing a role for SXR in common human malignancies will directly link environmental exposures and cancer because SXR is activated or antagonized by a variety of drugs and environmental chemicals. Three specific aims are proposed: (1) How does SXR loss-of-function lead to proliferation of B-1cells?, (2) Does inhibition of SXR by chemical antagonists lead to increased proliferation of B-1 cells and lymphoma?, (3) When is SXR action required in the developmental regulation of B-1 cell proliferation? Our studies will forge a link between SXR loss-of-function and lymphatic cancers, illuminating our understanding of how exposure to environmental chemicals such as PCBs alters gene expression to increase the risk of lymphoma and leukemia. Therefore, establishing a role for SXR in common human malignancies directly links environmental exposures and cancer. Exposure to endocrine disrupting chemicals is a continuing risk to the population; hence, these experiments will aid in elucidating a mechanism through which these environmentally relevant SXR modulators contribute to lymphomas. This knowledge will help to guide and focus future prevention efforts. Innovation The proposed research is innovative in that, to our knowledge, no one has yet provided a mechanistic link for how environmental exposures to organohalogen compounds such as PCBs and PBDEs are linked to blood cancers such as non-Hodgkin's lymphoma (NHL). Our published studies link SXR loss-of-function with NF-κB hyperactivity and chronic inflammation and we recently showed that SXR loss-of-function leads to a B-1a B cell lymphoma in mice. We employ an innovative mouse model, the humanized SXR knock-in (hSXRki) that expresses human SXR throughout the body under the control of the endogenous mouse promoter. This model allows us to test the novel hypothesis that inhibition of SXR function by chemical antagonists, in vivo, leads to lymphoproliferation and lymphoma.